This grant application proposes to evaluate the effects of prenatal exposure to a variety of centrally-active drugs, on the subsequent development of normal function of catecholamine, neuroendocrine and cardiovascular systems in the laboratory rat. Our proposed methods incorporate both a pharmacokinetic analysis of drug delivery to the fetus and a detailed evaluation of possible physiologic impairments subsequent to maternal drug exposure. In Project I we would critically test our hypothesis that lipid solubility is the primary determinant of the ability of drugs to cross the placenta and accumulate in the fetus. This would be accomplished by performing pharmacokinetic studies of the extent of fetal accumulation of drugs with a wide spectrum of lipid solubilities (i.e., octanol to water partition coefficient, PC). The following four drugs would be evaluated in this record: imipramine (PC=41,686), phenytoin (PC=295), phenobarbital (PC-26), and morphine (PC=6). In Project II, studies would be conducted to determine the subclinical teratogenic effects of maternal exposure to "non-teratogenic" doses of each of these drugs. Progeny of drug-treated pregnancies (and appropriate controls would be allowed to mature and test of the normal function of the neuroendocrine, cardiovascular and central nervous catecholaminergic systems would be performed. This experimental design would allow the determination of (i) the relationship between lipid solubility and fetal drug accumulation, (ii) the relationship between fetal drug levels and subclinical teratogenic effects of prenatal drug exposure, and (iii) the relationship (or lack thereof) of pharmacological mechanism of action and subclinical teratogenic effect. The proposed evaluation of the relationship between lipid solubility of drugs, their accumulation in the fetus and subsequent detrimental effect on progeny may provide a means of predicting the teratogenicity of drug and aid in the selection of appropriate drug therapy for pregnant women.